Bifunctional titanocene catalysis in multicomponent couplings: A convergent assembly of β-alkynyl Ketones

Article abstract of DOI:10.1021/ol400943a

Herein is described a titanium-catalyzed three-component coupling to assemble β-alkynyl ketones in a single operation. Treatment of an aryl aldehyde with an acetylide and silyl enol ether in the presence of a bifunctional titanocene catalyst enables the highly convergent assembly of β-alkynyl ketones in good to excellent yields.

Full text of DOI:10.1021/ol400943a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Bifunctional Titanocene Catalysis in
Multicomponent Couplings: A Convergent
Assembly of β‑Alkynyl Ketones
Catherine A. Campos, Joseph B. Gianino, and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame,
Indiana 46556, United States
bashfeld@nd.edu
Received April 5, 2013
ABSTRACT
Herein is described a titanium-catalyzed three-component coupling to assemble β-alkynyl ketones in a single operation. Treatment of an aryl
aldehyde with an acetylide and silyl enol ether in the presence of a bifunctional titanocene catalyst enables the highly convergent assembly of
β-alkynyl ketones in good to excellent yields.
The development of new transformations that rely on
relay catalysis and cascade bond formations has enabled
the rapid and convergent construction of highly versatile
syntheticbuilding blocks.1 However, despiterecent interest
in aryl-substituted β-alkynyl carbonyl derivatives for
pyran, furan, and pyrrole construction,2 most strategies
for their assembly employ linear sequences that rely on
sequential CÀC bond formations. Two common methods
involve either an enolate alkylation using a prefunctiona-
lized propargylic electrophile2d,3 or the conjugate addition
of an acetylide to an R,β-unsaturated carbonyl (Scheme 1a).4
Our recent work in multifunctional titanocene catalysis5
led us to speculate that a multicomponent coupling of
an aryl aldehyde 1, acetylide precursor 3, and silyl enol
ether 2 would result in a significantly more convergent
approach to the synthetically valuable aryl-substituted
β-alkynyl ketones 4 (Scheme 1b). The aryl-substituted
oxygen heterocycles bearing tertiary all-carbon centers
is a prevalent structural motif in nature, as exemplified
by calyxin L (5), epicalyxin F (6),6 brainin B (7),7 and
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r
10.1021/ol400943a
XXXX American Chemical Society

Additionally, the alkyne and carbonyl subunits are versa-
tile functional handles for a wide array of secondary trans-
formations. By using a single low-valent titanocene catalyst
to facilitate consecutive redox- and Lewis acid-catalyzed
transformations, we can access new CÀC bonds to effi-
ciently assemble this molecular architecture.9 Herein, we
report a highly convergent assembly of β-aryl γ-ynones
that exploits the redox and Lewis acidic properties of low-
valent titanocene using an aryl aldehyde as a traceless
dielectrophilic functionality.
Scheme 1. Approaches toward β-Alkynyl Ketones
Although our previous work5b,c on titanocene-catalyzed
multicomponent couplings indicates that the addition of
an enolate derivative would provide direct access to aryl-
substituted β-alkynyl ketones, the use of pregenerated
metal enolates is complicated by competitive formation
of aldol and aldol condensation products under the Lewis
acidic conditions of the coupling reaction. Acylation re-
sulting from attack of the intermediate propargylic acetate
by the enolate anion could hinder the desired coupling
event. Therefore, we began our studies by examining
silyl enol ethers as enolate surrogates, speculating that
their temperate reactivity would afford the desired three-
component coupling adduct. Gratifyingly, treatment of
aldehyde 1a, iodoalkyne 3a, and either TMS-enol ether 2a
or TES-enol ether 2b with Cp2TiCl2 (2 mol %), zinc dust,
(4-MeOC6H4)3P (40 mol %), and Ac2O provided ketone
4a in 78% and 73% yield, respectively (eq 1). With these
conditions in hand, we focused our attention on estab-
lishing functional group compatibility in the titanocene-
catalyzed multicomponent coupling reaction.
Aldehyde and iodoalkyne variability was examined by
coupling 1, 2aÀc, and 3 using our optimized conditions
(Table 1). Generally, good yields of the corresponding
ketones 4 were obtained for a diverse assortment of aryl
aldehydes and substituted iodoalkynes. The presence of an
aryl halide in aldehydes 1b and 1c did not negatively affect
the formation of ketones 4b and 4c (entries 1 and 2).
Electron-rich aryl aldehyde 1d also provided the corre-
sponding ketone 4d in 78% yield (entry 3). TIPS silyl enol
ether2c and thiophene 1e proved effective in the titanocene-
catalyzed coupling with 3a to give ketone 4e in 75% yield
(entry 4). Aryl- and alkyl-substituted alkynyliodides3b, 3c,
and 3d reacted efficiently with aldehydes 1a and 1f, respec-
tively, to yield ketones 4fÀh (entries 5À7). It is particularly
noteworthy that the primary propargylic acetate in 3e
remained intact throughout the coupling to give ketone
4i indicating exceptional chemoselectivity for alkylation of
the more substituted secondary acetate intermediate (entry 8).
Finally, employing the acetylene surrogate, TIPS-iodoalkyne
3f, yielded ketone 4j in 66% yield (entry 9).
Figure 1. Biologically active heterocyclic natural products.
kurzichalcolactone A (8)8 (Figure 1). The intriguing bio-
logical properties associated with these natural products
make this architectural subunit an important target for
synthesis. A multicomponent coupling approach toward
aryl-substituted β-alkynyl carbonyl construction results in
a flexible and modular assembly of this heterocyclic motif.
(8) Dumontet, V.; Hung, N. V.; Adeline, M.-T.; Riche, C.; Chiaroni,
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1289. (e) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc.
To establish the functional variability of the silyl enol
ether component, aldehydes 1a and 1d were treated with
1998, 120, 12849. (f) Dang, Y.; Geise, H. J. J. Organomet. Chem. 1991,
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B
Org. Lett., Vol. XX, No. XX, XXXX

Employing the alkyl-substituted iodoalkyne 3d did not
adversely affect the yield of ketone 4n formation (entry 4).
Additionally, the aldehyde-derived silyl enol ether 2g under-
went alkylation with aldehyde 1a and iodoalkyne 3a to yield
adduct 4o in 78% yield (entry 5). It is particularly note-
worthy that none of the corresponding aldol product
resulting from addition of residual enol ether 2g to alde-
hyde 4o was observed in the reaction. Attempts at subject-
ing silyl ketene acetals to the reaction conditions resulted in
formation of a complex mixture of compounds with no
desired ester product detectable.
Table 1. Aldehyde and Iodoalkyne Compatibilitya
Table 2. Silyl Enol Ether Variabilitya
a Conditions: same as in Table 1. b Isolated yields. c Product obtained
as a 1:1 mixture of diastereomers. d 80 mol % (4-MeOC6H4)3P used.
Although silyl enol ethers 2aÀg participated in the
multicomponent coupling to yield products resulting from
R-C-alkylation, vinylogous enol ethers underwent exclu-
sive γ-alkylation. For example, the titanocene-catalyzed
coupling of silyloxy furan 2h with aldehyde 1f and
a Conditions: 1 (0.5 mmol), 2a (0.65 mmol), 3 (0.6 mmol), Cp2TiCl2
(2 mol %), Zn (1.05 mmol), (4-MeOC6H4)3P (40 mol %), Ac2O (0.55
mmol). b Isolated yields. c 25 mol % (4-MeOC6H4)3P used. d Enol ether
2c (0.6 mmol) employed. e 80 mol % (4-MeOC6H4)3P used.
either iodoalkyne 3a or 3d and silyl enol ethers 2 to provide
the corresponding β-alkynyl ketones 4 in good yields
(Table 2). Enol ether 2d derived from acetone proved
effective in the formation of ketone 4k (entry 1). Silyl enol
ethers bearing substituents at the R-position were also
tolerated in the coupling reaction. Both the Z-enol ether
2e and E-enol ether 2f reacted with aldehydes 1a and 1d
respectively, to yield the corresponding ketones 4l and 4m in
67% yield as a 1:1 mixture of diastereomers (entries 2 and 3).
(10) (a) Ogata, A.; Nemoto, M.; Kobayashi, K.; Tsubouchi, A.;
€
Takeda, T. Chem.;Eur. J. 2007, 13, 1320. (b) Gansauer, A.; Barchuk,
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Org. Lett., Vol. XX, No. XX, XXXX
C

iodoalkyne 3a provided butenolide 4p in 60% yield as a 1:1
mixture of diastereomers (eq 2).
role of phosphine is the subject of current investigation
and will be reported in due course.
Scheme 2. Relay Catalysis in CÀC Bond Formations
R,β-Unsaturated aldehydes were also effective sub-
strates in the multicomponent assembly of β-disubstituted
ketones. Coupling enal 9, enol ether 2a, and iodoalkyne 3a
under our optimized conditions afforded isomeric ketones
10a and 10b in a 1:1 ratio (eq 3). The lack of regio-
selectivity in the enol ether alkylation indicates the pos-
sibility of an electrophilic allyl intermediate where there is
little to no preference for alkylation at either allylic terminus.
On the basis of these results, a possible relay mecha-
nism for the three-component coupling involves initial
Cp2TiIIIX-catalyzed zincation of iodoalkyne 3a to yield
zinc acetylide 11 and Cp2TiIVX2 (Scheme 2).12 Addition of
11 to aldehyde 1a followed by in situ acylation with Ac2O
provides propargylic acetate 12. Activation of 12 by Lewis
acidic Cp2TiIVX2 results in propargylation of silyl enol
ether 2a most likely via a cationic open transition state. It is
important to note that the ZnIIX2 salts generated in the
metalationÀcarbonyl addition event may also participate
in the Lewis acid-mediated propargylic substitution. How-
ever, an alternative mechanism formation of a propargylic
titanocene intermediate from acetate 12 followed by a re-
ductive coupling with silyl enol ether 2 cannot be ruled out.
In summary, we have developed a titanocene-catalyzed
multicomponent coupling approach toward the highly
convergent assembly of β-alkynyl ketones from readily
available aldehydes, silyl enol ethers, and iodoalkynes.
Through consecutive CÀX/CÀO activations facilitated
by a bifunctional titanocene catalyst, two new CÀC bonds
are generated in a single operation using aldehydes as
a traceless, dielectrophilic functionality. The resulting
β-alkynyl ketones are known to be versatile building
blocks in the construction of heterocyclic architectures
prevalent in natural products. Mechanistic studies and
the application of this method in total synthesis are
currently being pursued and will be reported in due course.
Consistent with our previously reported studies,5 there
appears to be a synergistic effect of Cp2TiCl2, Zn0, and
tBu3P in both CÀC bond-forming steps.9e,10 Omission of
both Cp2TiCl2 and Zn0 led to recovered aldehyde 1b after
2 h at rt. Although the presence of Zn0 and phosphine in the
absenceofCp2TiCl2 provided the intermediate propargylic
alcohol after extended periods of time (>24 h), subsequent
silyl enol ether alkylation was not observed. Perhaps most
interesting was the effect of phosphine concentration on
the reaction outcome. Our empirical observations point to
phosphine having a positive impact on the initial iodoalk-
yne metalation and carbonyl addition steps, while higher
concentrations of phosphine hindered the subsequent enol
ether alkylation. For example, in the coupling of aldehyde
1a, enol ether 2a, and iodoalkyne 3c, increasing the
concentration of phosphine (80 mol %) had an adverse
effect leading to 41% yield of 4g and 47% of the corre-
sponding propargylic acetate intermediate. This is consis-
tent with our hypothesis that the presence of phosphine
promotes iodoalkyne metalÀhalogen exchange and addi-
tion to the aldehyde through an unusual ZnÀP ligation.11
However, an abundance of phosphine can lead to
saturation of the TiIV complexes and ZnII salts present,
ultimately hindering the Lewis acid-catalyzed pro-
pargylic ionization step necessary for enol ether alkyla-
tion. Although PPh3 successfully provided 4a in
74% yield, other phosphines failed to approach the
efficiencies observed with (4-MeOC6H4)3P. The exact
Acknowledgment. We thank the University of Notre
Dame for financial support of this work.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX